Design, Optimization and Mechanistic Insights Into Terpenoid‐Derived Inhibitors of Protein Kinase C Iota

ABSTRACT

Protein kinase C iota (PKCι) is an atypical PKC isoform overexpressed in several human cancers and associated with tumor initiation, maintenance, and resistance to therapy. Meroxest, a synthetic naphthoquinone merosesquiterpene previously shown to exert antitumor activity in breast cancer models, has an incompletely defined mechanism of action. Here, we profiled meroxest against a 410‐kinase panel and synthesized a focused set of analogues to obtain preliminary PKCι‐oriented structure–activity information. At 10 μM, meroxest reduced PKCι enzymatic activity to 52% of control and Cdc7/cyclin B1 activity to 63%, identifying PKCι as the most inhibited kinase in the panel while also indicating that additional kinase targets may contribute to the biological activity of this scaffold. Docking studies supported a plausible interaction of meroxest within the PKCι catalytic site, including hydrogen‐bond contacts with Gly398 and Phe423 consistent with an ATP‐competitive binding mode. Biochemical evaluation of a focused library against PKCι at 10 μM showed that preservation of the quinone framework was important for activity, whereas most structural modifications produced only limited changes under the assay conditions used. Compound 19 , lacking the methyl substituent on the naphthoquinone ring, showed a modest improvement relative to meroxest. Overall, these results support PKCι as a leading candidate target emerging from the meroxest kinase profile and identify compound 19 as a scaffold for further optimization. Future studies will focus on further optimization to improve the modest PKCι inhibitory potency, evaluate activity against Cdc7/cyclin B1 beyond the parent compound, and validate target engagement in cell‐based assays, aiming to identify optimal candidates.